Astrocytes are the most abundant cell type in the CNS that play vital roles in all facets of brain physiology. Activation of astrocytes, or reactive astrogliosis, is associated with morphological, gene expression, and functional alterations. Although changes in astrocyte dynamics a common feature in Alzheimer's disease (AD), its underlying mechanisms and functional consequences remains poorly understood. Our recent studies identified five astrocyte subpopulations that display diverse molecular and functional characteristics in the brain. Significantly, one of the subpopulations, the synaptogenic astrocytes, strongly correlated with human AD expression datasets. This is exciting because synaptic dysfunction is widely accepted as an early and causal event in AD pathogenesis. Our long term goal is to decode the astrocyte types and determine the impact of the diverse astrocyte populations in aging and AD. The objectives of this proposal are to define the cellular and molecular heterogeneity of astrocytes in the cortex and hippocampus and to ascertain the functional role of synaptogenic astrocytes during aging and in AD mouse models. We hypothesize that diverse astrocyte subpopulations in the adult brain differentially contribute to AD pathogenesis and that reduced function of synaptogenic astrocytes plays a crucial role in driving synaptic dysfunction in early AD. To test the hypotheses we will profile changes of astrocyte subpopulations and define their molecular signatures in wild-type mice and AD mouse models as a function of age and AD pathology and cross-validate these results in postmortem human samples and associated expression datasets. We will decipher the role of synaptogenic astrocytes in AD pathogenesis by genetic targeting and functional testing of selected candidates. These studies will be led by two investigators with exceptional track-record in astrocyte biology (Deneen) and AD pathophysiology (Zheng) and assisted by outstanding bioinformatics support. Overall the proposal will significantly advance our understanding of astrocyte heterogeneity in brain regions critical to AD and how early and late astrocyte dysfunction contributes to AD pathogenesis. It will also lead to the identification of novel biomarkers and therapeutic targets.